Relationship between omalizumab pharmacokinetics and IgE pharmacodynamics in adult and pediatric patients with moderate to severe persistent allergic (IgE-mediated) asthma
Stacey Tannenbaum[2], Aurelie Gautier[1] & Philip Lowe[1]
[1]Novartis Pharma AG, 4002 Basel, Switzerland; [2]Novartis Pharmaceuticals Inc, East Hanover, New Jersey, USA
Objectives: To use a population-based PK-binding model that describes the binding and turnover of omalizumab and IgE to compare the kinetics of omalizumab and IgE in pediatric patients with adults.
Methods: Omalizumab, free IgE, and total IgE plasma concentrations were measured in patients from six clinical studies. Single dose data from a bioequivalence study were also included to confirm that the model captured the rapid suppression of free IgE and the return to baseline following treatment cessation.
These data were fitted to a dynamic drug-ligand binding and turnover model based on the omalizumab-IgE binding reaction; the model integrated drug and IgE inputs and elimination together with binding affinity. The model was written as differential equations in NONMEM. Typical values of the parameters and intersubject variability terms were estimated. Bodyweight and baseline IgE were included as covariates based upon prior work; other potential covariates such as age were explored graphically.
Results: The model fitted well both single-dose data from healthy but atopic volunteers and longer-term multiple-dose data from patients with severe persistent allergic asthma. All parameters were scaled to body weight; once weight was accounted for, the relationships between age and the posthoc estimated ETA values for the parameters did not show a notable trend.
For a typical subject weighing 70 kg and with a baseline IgE of 365 ng/mL, CL/F and V/F for omalizumab were 0.196±0.003 L/d and 8.07±0.192 L. The clearance of free IgE was 2.68±0.387 L/d and the clearance and volume of the omalizumab-IgE complex were 0.613 ± 0.0857 L/d and 2.13±0.42 L, respectively. The model estimated the production rate of IgE to be 857±122 µg/d and the binding affinity of omalizumab to IgE to be 1.84±0.071 nM.
A predictive check demonstrated that the model had the ability to predict both the central tendency and the distribution of exposure to omalizumab, the increase in total IgE, and the suppression of free IgE across the omalizumab bodyweight and baseline IgE based dosing table.
Conclusions: A population-based PK-binding model was fitted to free IgE, omalizumab and total IgE concentrations from six clinical studies. Both adult and pediatric data fitted well, and it was determined that once differences in bodyweight and baseline IgE are taken into account, pediatric allergic asthmatic patients were not different from adults in terms of parameters of monoclonal antibody disposition and target binding.